Central (visceral) obesity contributes to an excess risk of diabetes, dyslipidemia, and death from coronary heart disease in men and women. Hypogonadism in both men and women typically leads to central obesity but the mechanisms causing this change in fat distribution are poorly understood. Data presented here support a role for sex steroid regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the expression of visceral obesity in men and women. Recent studies also suggest a role for enhanced conversion of cortisone to cortisol in the adipocyte by the enzyme 11 b-hydroxysteroid dehydrogenase 1 (HSD 1) in the expression of visceral adiposity and insulin resistance. The first aim of this grant is, therefore, to prospectively determine if sex steroids (estrogen in women, testosterone in men) regulate HPA activity, systemic free-cortisol levels, HSD 1 activity in fat biopsies and in the whole body by quantifying urinary glucocorticoid metabolites, and intracellular cortisol levels and glucocorticoid receptor binding capacity in adipocytes. Sequential follow-up study visits will determine the time course of these hormonal effects on these outcomes. In addition, based on evidence indicating that subjects with central (visceral) obesity have "ectopic" triglyceride deposition in muscle and fat, and that these depositions may play an etiological role in insulin resistance in these tissues, magnetic resonance spectroscopy (MRS) will be used to quantify intramyocellular (IMCL) and intrahepatic fat (IHF), along with measures of visceral fat by CT scan, in these subjects. Availability of the MRS technique offers a unique opportunity to non-invasively study mechanisms that might result in ectopic fat deposition and insulin resistance. Therefore, the second aim of this grant is to include measurements of central fat patterning by CT, ectopic fat deposition in muscle and liver by MRS, and measurement of insulin sensitivity in the subjects undergoing sex steroid hormonal therapy. Understanding the physiology resulting in the expression of central obesity and insulin resistance will be important in developing new tools to treat these disorders and in the prevention of diabetes and cardiovascular risk in men and women.